The proposed U54 Center at Virginia will have a major goal of promoting translational research leading to application of new basic findings to clinical application. The Center theme is "Clinical and Basic Studies in Polycystic Ovarian Syndrome (PCOS)." This topic is appropriate to the goals of the Cooperative Centers Program, in that present therapeutic approaches to the anovulation and metabolic abnormalities in the disorder are of limited efficacy, and importantly, the basic mechanisms underlying PCOS remain uncertain. Current hypotheses as to of the etiology of PCOS center around regulation of GnRH secretion and action, and/or disordered ovarian function, either primary in nature or consequent to abnormal stimulation by gonadotropins or co-gonadotropins such as insulin and IGF-I. The U54 Center proposes two clinical and two related basic projects to investigate these areas. Project I addresses abnormalities in regulation of the GnRH pulse generator in women and is directly related to basic studies in Projects II, on cellular mechanisms of GnRH frequency and steroid regulation of gonadotropin gene expression, and Project III on steroid and neurotransmitter regulation of firing patterns of GnRH neurons. Project IV (contract with Virginia Commonwealth University), addresses the clinical effects of reduction of hyperinsulinemia on cyclic hormonal profiles, ovulation and endometrial function. The Center subprojects are supported by three Cores proposed to operate under an "open access" formula. Overall integration of the research will be performed by the Administration Core, and specific laboratory services will be available to U54 projects and to eligible funded Reproductive Sciences Branch (RSB) program relevant projects through Molecular Biology and Ligand Assay and Analysis Cores. The proposed U54 Center will build on the productive collegial atmosphere of the existing U54 Center at Virginia and allow clinical and basic investigation of a common disorder of women during the reproductive years. The linking of basic and clinical projects will allow rapid transfer of basic information to clinical application, with the overall goal of enhancing our therapeutic approach to PCOS with a resultant improvement in health for women in the U.S.